I had a good talk with Virginia Falkenburg and other CDC researchers at the Ottawa conference, and we have communicated by email since. She is working on a genome-wide methylation study in ME/CFS, and was interested in the methylation deficit that we have found. It will be very interesting to see how her study comes out. I would expect that there would be an overall trend toward upregulation of gene expression in ME/CFS, since methylation tends to silence gene expression, and less of that should be occurring. This was seen in Jonathan Kerr's study. Time will tell how it will come out in the CDC study.

With regard to perforin, I continue to suggest that the low perforin output of NK and CD8 cells in ME/CFS is due to glutathione depletion, which is linked to the methylation cycle partial block by a vicious circle mechanism. The methylation deficit might tend to raise the gene expression of perforin, but the glutathione depletion would act in the other direction, because perforin has 20 cysteine residues, and glutathione is needed to keep cysteine from oxidizing to cystine before the appointed time in the protein synthesis process. So the situation is complicated. We have to consider what is happening at both the genetic and the biochemical levels. At the conference, I suggested to the gene expression researchers that the fundamental issue in ME/CFS begins at the biochemical level, and the changes in gene expression result from that. This seems backward to some people, because the enzymes that carry on the biochemistry result from expression of the genes. So the genes and their expression seems more fundamental. However, there is considerable interaction between the two domains, especially when the methylation cycle in the biochemistry is involved, because it has major effects back on the gene expression.

I'm really happy that the gene expression researchers are starting to consider the effects of methylation on gene expression in ME/CFS. It will be interesting to see how this comes out.

On methylation blocks and glutathione: if a block exists in methylation for most of us, it is possible that certain tissues have little if any problems, and some tissues have major problems. During differentiation into different cell types, many genes are silenced and some become preferentially expressed. Cells have different capacity to adapt to things, so I expect some cells will have more capacity to adapt to low glutathione. As a result, as in so much of of ME research, I think we have to move away from blood and start looking at target tissue biopsies, particularly gut and lymph nodes. Obviously we don't want to biopsy spine or brain, so gut and lymph node will have to do.

Under this hypothesis a slight methylation cycle block could actually be major, particularly for cell types that cannot import glutathione. This is because relatively uneffected cells might be OK, and help stabilize total serum glutathione (hence look like glutathione is normal) but other cells may have very little glutathione. Also at risk would be cells that utilize lots of glutathione, and NK cells might be one of these. I have been thinking about this problem of blood averaging cell results for a very long time, but have yet to come to any firm conclusions. It was one of the driving factors behind my getting my biochem degree, more than a decade ago. The time of blood is over I think, we need to focus on tissues starting with those that are associated with symptomology.

I think you are right about different cell types responding differently when there is a bodywide glutathione depletion and partial methylation cycle block.

One way I think this happens is that only a few organs are known to have a complete and rapidly operating transsulfuration pathway, and are thus able to readily convert methionine into cysteine, which is usually the rate-limiting amino acid for the synthesis of glutathione. So these organs are in a better position to keep their glutathione up than are other organs. Those known to have this capability are the liver, kidneys, pancreas, intestine, lens of the eye, and to a much lesser degree, the brain. I think it is thus no coincidence that the symptoms of ME/CFS appear to be associated with the skeletal muscles, the heart muscle, the immune system, the nervous system, and part of the endocrine system (not including the endocrine pancreas). The most vital organs appear to be able to protect themselves more effectively in this regard, thus preserving life.

I think you are right about different cell types responding differently when there is a bodywide glutathione depletion and partial methylation cycle block.

One way I think this happens is that only a few organs are known to have a complete and rapidly operating transsulfuration pathway, and are thus able to readily convert methionine into cysteine, which is usually the rate-limiting amino acid for the synthesis of glutathione. So these organs are in a better position to keep their glutathione up than are other organs. Those known to have this capability are the liver, kidneys, pancreas, intestine, lens of the eye, and to a much lesser degree, the brain. I think it is thus no coincidence that the symptoms of ME/CFS appear to be associated with the skeletal muscles, the heart muscle, the immune system, the nervous system, and part of the endocrine system (not including the endocrine pancreas). The most vital organs appear to be able to protect themselves more effectively in this regard, thus preserving life.

Best regards,

Rich

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Hi Rich,

Over and over in reading the research on b12 it is stated that the body has some sort of triage system for providing some functions with b12 while starving others. There is not an even or roundrobin deprivations. Some functions will be supplied and some will be starved. It might very well work that way for other substances as well.

Over and over in reading the research on b12 it is stated that the body has some sort of triage system for providing some functions with b12 while starving others. There is not an even or roundrobin deprivations. Some functions will be supplied and some will be starved. It might very well work that way for other substances as well.

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Hi, Freddd.

Yes, there is a built-in triage or priority system for (I suspect) every substance that the body needs. The relative values of the Michaelis constants are quantitative expressions of this. This may be one of the reasons why the structures of enzymes are so complex. They may need to be complex in order to be able to incorporate the priority system as well as carrying out their other functions. Speaking as someone who was trained in engineering, it's really an incredible design, in my opinion.

So, Rich, given your triage idea, why do we have such difficulty with aerobics and oxygen insufficiency? Is the problem to do with our respiratory muscle system rather than our actual lungs?

Lynne

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Hi, Lynne.

I think that some PWMEs might have difficulty breathing because of mitochondrial dysfunction in the muscles used for breathing. This could produce a sensation of "air hunger." As far as I know, the lungs themselves are usually O.K.

There are others whose bodies do not demand as much oxygen as normal, because of mitochondrial dysfunction in the skeletal muscles and other tissues. This can cause a low rate of use of oxygen and a low rate of production of CO2. Since the respiratory center in the brainstem governs the rate and depth of breathing based on carbon dioxide level and pH of the blood it receives, this can cause a slowing and shallowing of the breathing. Some PWMEs report that they find that they "forget to breathe," and I think this is the reason.

Dr. Cheney reports that his patients actually have "oxygen toxicity." That is, if he gives them more oxygen using a mask, he observes that the diastolic dysfunction of their hearts worsens.

I think that the reason PWMEs are not about to do aerobic exercise very well is again because of mito dysfunction. Aerobic exercise requires a high rate of production of ATP to power the muscle contractions. By far most of the ATP is normally produced by the mitochondria. If they aren't working well, this high rate of production is not going to happen.

In my hypothesis, the mito dysfunction in turn is due to the vicious circle mechanism involving glutathione depletion, a functional B12 deficiency, a partial block in the methylation cycle, and loss of folates from the cells.

so it sounds like her study will give you/her plenty of information to digest & use to inform your theory?

It's wonderful to hear that you have and continue to communicate with her.

Is Methylation/gene expression another chicken-egg thing? i.e. -which comes first and one affects the other???

Do you know of any good a learning sources on the subject for us uninformed?

Thanks again.

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Hi, voner.

Sorry, I don't know of a good writeup on methylation and gene expression and which comes first. I think this subject is more or less at the cutting edge of research at the moment.
I don't think the gene expression researchers have considered up to now that there might be a partial block in the methylation cycle at the biochemical level. The issue of the partial block in the methylation cycle was (I think) discovered only in 2004 by S. Jill James et al. in autism research, and it is yet to be fully realized and understood by the research community.

I think this is sort of analogous to the situation with creatinine in urine testing. In the past, it has been common to divide the concentrations of other substances in the urine by the concentration of creatinine, because the latter was considered to be more or less invariant, so that it could be used to normalize the levels of the others, in order to compensate for differing amounts of water diluting the urine, depending on each person's water balance at the time of testing. However, in ME/CFS and in autism, because of the methylation deficit, and because the synthesis of creatine, the precursor of creatinine, is the main user of methylation in the body, the rate of excretion of creatinine can vary from the norm. I don't think this has totally sunk in yet, either.

Sorry, I don't know of a good writeup on methylation and gene expression and which comes first. I think this subject is more or less at the cutting edge of research at the moment.
I don't think the gene expression researchers have considered up to now that there might be a partial block in the methylation cycle at the biochemical level. The issue of the partial block in the methylation cycle was (I think) discovered only in 2004 by S. Jill James et al. in autism research, and it is yet to be fully realized and understood by the research community.

I think this is sort of analogous to the situation with creatinine in urine testing. In the past, it has been common to divide the concentrations of other substances in the urine by the concentration of creatinine, because the latter was considered to be more or less invariant, so that it could be used to normalize the levels of the others, in order to compensate for differing amounts of water diluting the urine, depending on each person's water balance at the time of testing. However, in ME/CFS and in autism, because of the methylation deficit, and because the synthesis of creatine, the precursor of creatinine, is the main user of methylation in the body, the rate of excretion of creatinine can vary from the norm. I don't think this has totally sunk in yet, either.

Best regards,

Rich

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Rich, the standard test now for kidney function is the GFR, which is a ratio with creatinine, isn't it? As a PWME and also "partial central diabetes insipidus", I wonder if my abnormally low GFR means I am in 3rd stage kidney disease, as the standard chart would have it, or if this might be another
abnormality in the ME picture, which could mean something else? Any thoughts?

So, Rich, given your triage idea, why do we have such difficulty with aerobics and oxygen insufficiency? Is the problem to do with our respiratory muscle system rather than our actual lungs?

Lynne

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Hi Lynne,

It took 2 specific things for my lack of aerobic capability. I atarted out with essentially zero capcity and nothing changed it. When I took adb12 I had a big increase and after a year got up to 17 minutes on the Nordic trak and hit the wall. Then I added l-carnitine fumarate and my aerobic capacity literally doubled overnight, to 34 minutes. From there on my muscles started growing and I was able to keep moving the time up and up or increasing the intensity. My thigh muscle on top of the leg increased from the thicknees of my thumb back to a full hand span in about 2 years. Before that nothing affected it. Further all the various differnt pains from the specific 18 tender points to constanrt aching and burning, very tight and spasming frequently. All gone. Good luck. Adb12 does things that mb12, hydroxycbl and cyancbl can't do. It has to do with the TYPE of cobalamin. Unlimited methylb12 didn't do the trick. It could not bring the mitochondroia up to full speed.

That's impressive! Do you mind expanding the names for me? For instance, what are adb12, mb12, hydroxycbl and cyancbl?

cheers, Lynne

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Hi Lynne,

Adb12- adebosylcobalamin - powers mitochondria to make ATP and processes fats for making myelin
Mb12 - methylcobalamin - used in neurological funtioning, cell formation, immune system, hormones, healing everything everything else b12 does
hydroxycbl - hydroxcobalamin - a minor transitory cobalamin from breakdown of methylb12/adenosylb12 and some very small amount can be salvaged/reprocessed into active b12, as starvation mode
cyanocbl - cyanocobalamin - waste product form of cobalamin preferred by kidneys for excretion after detoxing cyanide in the body and some very small amount can be salvaged/reprocessed into active b12, as starvation mode. Discovered instead of methylb12/adenosylb12 in 1948 becasue of lab mistake. Corrected 11 years later when xray crystalography identifed the two major forms of b12 in the body as methylb12 and adenosylb12. There are another dozen or more trace temporary and/or plant cobalamins, all completely inactive and nontoxic, found in the body after detoxifying any number of other toxins etc.

cyancbl- typo of cyanocbl

I do not use "b12" to stand for cobalamin in either of the two inactive cobalamins that convert to a very limited extent to the real b12s. I guess I could call it 1% - b12 because they are at best about 1% as effective. I just can't call them b12 even though cyanocobalamin is the OFFICIAL "b12" and everything else are "b12 analogs" because that would be like calling a Twinkie "complete healthful nutrition".

This is interesting, Creatine is a supp I've recently added and has shown some benefit even in very small doses. Thanks Rich

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Interesting. Although not using it now, i have had more success with creatine then ribose which is normally recommended. Creatine is suppose to help delay fatigue and help recycle ADP into ATP if my memory is correct.

Thank you for your replies and other peoples replies also. Certainly enlightening. It is nice to see Alex reply -- someone else with biochemistry knowledge.

So is Virginia Falkenburg and other CDC researchers going to look at gene expression in the methylation cycle? Do you know exactly what what they are looking at and why? do you think this research of Virginia's group is going to tell you much?

As two side comments

what do you think of Alex's dislike of the researchers using blood samples? I understand that blood samples are much easier to take and process etc.

When I look at me/cfs/fms - I also think about the common dysfunction in the intestinal digestion.. commonly called irritable bowel syndrome etc. This certainly indicates some sort of dysfunction in the intestine -- does it involve methylation? Or is something else going on there with absorption of vitamin B12??

Thank you for your replies and other peoples replies also. Certainly enlightening. It is nice to see Alex reply -- someone else with biochemistry knowledge.

So is Virginia Falkenburg and other CDC researchers going to look at gene expression in the methylation cycle? Do you know exactly what what they are looking at and why? do you think this research of Virginia's group is going to tell you much?

As two side comments

what do you think of Alex's dislike of the researchers using blood samples? I understand that blood samples are much easier to take and process etc.

When I look at me/cfs/fms - I also think about the common dysfunction in the intestinal digestion.. commonly called irritable bowel syndrome etc. This certainly indicates some sort of dysfunction in the intestine -- does it involve methylation? Or is something else going on there with absorption of vitamin B12??

voner...

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Hi Voner,

IBS, I know it well. I've had it for 50 years. While methylb12 sometimes allowed it to go away for a while, the thing that can predictably bring it back over and over for me is folate deficiency and with enough metafolin without folinic, folic, NAC, glutathione, it can be gone in 5 days. I suspect it is one of my quickest and most reliable indicators if methylation is happening in my body. It is rapidly dividing epithelial cells in the intestine and appears very sensitive to folate and mb12 problems. It is my conjecture that it is methylation but maybe it is some other failure cause by lack of folate. Of course I also get tissue breakdown at the corners of my mouth and my finget tips around nails at the same time so it seems like the more generalized cell reproduction failure that one would see first in the fastest reproducing cells where there is a lot of wear and tear.

Just these past few months have been a real eyeopener. With the mb12 it was always kind of iffy if the IBS was going to be affected. With the methylfolate, it is ALWAYS affected if I remove the the folate containing things which these days are too many veggies, from my diet. I can eat salad or yellow squash or steamed carrots, or whatever veggies I want. If I have two servings it starts to get iffy and If i eat pure vegetarian for a day or have 3 servings for a couple of days folate deficiency comes bounding back with IBS. There is now a 100% correlation. I can make it happen and I can get rid of it. The difficult part is eating all the veggies I like and NOT having folate deficiency and IBS.

Yes, there is a built-in triage or priority system for (I suspect) every substance that the body needs. The relative values of the Michaelis constants are quantitative expressions of this. This may be one of the reasons why the structures of enzymes are so complex. They may need to be complex in order to be able to incorporate the priority system as well as carrying out their other functions. Speaking as someone who was trained in engineering, it's really an incredible design, in my opinion.

Best regards,

Rich

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Hi Rich,

I agree, an incredible design with multiple pathways for many things with complex interacting negative feedback systems. The references I have seen appears to indicate a surprise that the triage system is so much more complex for the b12 B12 appears to be the "most limiting factor" gnerally in almost every system of the body. It's the only one that typically exists at the bare minimum for adequate function. It appears to be the only vitamin that has rather extravagant "starvation mode" systems for the expensive (ATP plus an enzyme) reclaimation of b12 from some waste forms of cobalamin. On the other hand when a person becomes too depleted to recover under natural circumstances another set of effects come along to kill them off faster, ie blood that goes wrong in many ways, failing immune system, constant diarhea and nutrient specific anorexia for b12 and only b12. Evolutionarily this gets into survival of the family/tribe rather than only the individual.

Oliver Wendell Holmes, Sr. memorialized the shay in his light poem "The Deacon's Masterpiece or The Wonderful One-Hoss Shay". The fictional deacon built this wonderful one horse shay so it wouldn't break down. He built it from the very best of materials so that each part was as strong as every other part. In Holmes' humorous, yet "logical", twist, the shay endures for a hundred years to the day (actually to the moment of the 100th year of the Lisbon Earthquake to the precise hour of the earthquake shock) then it "went to pieces all at once, and nothing first, just as bubbles do when they burst." It was built in such a "logical way" that it ran a hundred years to a day.